How do cells know whowhat to adhere to 1112

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How do cells know who/what to adhere to? 11/12

• Three copies of your rough draft due at start of
  class today!

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Tendons consist of extracellular proteins. They
are composed of collagen fibers that are produced
by fibroblasts (exocytosis). Collagen fibers
are arranged in a staggered overlapping pattern
of fibrils.
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Disulfide bonds are critical for the cross-links
that strengthen collagen! Vitamin C (ascorbate)
promotes oxidation of the sulfhydryl groups!
Collagen forms a matrix around which other cells
and bone may organize.
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Rubbery elastin stretches and snaps back into the
original shape! It is rich in negative charges
that repel each other to help prevent excess
stretching and to help it snap back.
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Glycocalyx provides a critical carbohydrate
matrix that sits between a cells plasma
membrane and the external environment. It also
contains a series of glycoproteins whose protein
segments mediate enzymatic digestion.
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Cartilage is a proteoglycan (modified ground
substance) that contains varying amounts of
collagen and elastin, depending on its location
and function. The function of cartilage in a
joint is to provide a watery surface across which
joints can move across with minimal friction.The
function of cartilage in your ear is to be able
to return to its original shape.The function of
cartilage in a vertebral disc is to resist
rupture.
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Why is cell-cell adhesion so important to
understand?

• Migrating cells must reach, recognize, bind and
  stay with their target cells, tissues and organs!
• Important implications in embryogenesis, cancer,
  infection, transplantation potentials (stem
  cells) and disease!
• Tissue Development in the Embryo/Adult
• Epithelial cell to basal lamina post burn
  skin
• Neural crest cell in embryo amputee
  nervous system
• Endothelium and blood vessels cancer
• Pathway Guidance to Lead Cells Home
• Chemotaxis vs. Chemo-avoidance
• Ligands/Receptors/Second Messengers
• N-CAMS and transmembrane adhesion molecules help
  mediate binding of cells to the ECM and each
  other!

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Embryogenesis is the development of tissues and
organs. This is a review of embryonic
development in a chick, similar process also
occur in human embryos.
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There are a variety of options available to cells
when they seek to bind to other cells or know if
they are in the correct location. Lets review
some of the options available. Know one item that
makes each unique.

• N-CAMS CaIndependent
• Bind to other N-CAMS
• Cadherins Ca-Dependent
• Bind to other cadherins
• Selectins dont bind each other. Specialized to
  bind target glycoproteins
• Intergrins bind laminin of the basal lamina or
  fibronectin in the ECM or to other cells.

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Cadherins are a class of CaDependent cell-cell
adhesion molecules which are important in
embryogenesis. Their loss permits cells to
migrate within the chick embryo to become muscle.

• Dimer anchored by tx-membrane sequences
• Localization of sub-types
• E-epithelial N-neuronal
  P-placental VE-endothelial
• For instance N-cadherin binds to
  other N-cadherins, but not to E, P or
  VE-cadherins
• This keeps neurons attached to other
  neurons!
• Important to vertebrates and invertebrate animals
• Classic exrracellular Cadherin binds to actin on
  intracellular side.
• Non-Classic binds tonofilament on inside for
  extra strength
• If potential neurons dont lose N-cadherins, they
  cant migrate!
• About 85 of cancers are epithelial in nature
  (due to high replication rate), metastasis is
  linked to a loss of E-cadherins

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White blood cells tend to Roll along the
surface of blood vessels looking for trouble (a
signal of damage outside vessel). When damage
occurs endothelial cells move P-selectin from
vesicle to the cell surface and this binds the
leukocyte glycoproteins! Then integrin binds its
ICAM!
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What amino acids would you expect at the
locations where the glycosylations occur on
glycophorin? Why is the carbohydrate sialic acid
(-charged) important for the extracellular side
on an RBC? When the erythrocyte has circulated
for about 60-120 days, the sialic acids and
glycosylations will have rubbed off to expose the
receptor, which mediate lysis in the spleen or
liver. This
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How does the body know when to destroy a red
blood cell that is 120 days old or older?
Solution selective removal of RBC sialic acids.

• What does sialic acid,also called
  N-acetylneuraminic acid (NANA), look like?
• What is its net charge?
• NANA attached to glycoprotein Neuraminase
  removes NANA
• No NANA N-CAM Exposed!
• Cell binds to macrophage
• Removal at spleen/liver
• 120 day life-span
• 1 trillion RBCs in the body 1 million cells
  removed/second
• 1 pint/30-60 days!

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Fibronectin is an important mediator between
cells and the contents of the matrix.

• Generally found as a extracellular dimer
  crosslinked by a pair of dissulfides (-S-S-)
• Each subunit (dimer) contains different domains,
  each domain has a potentially different function.
• Sample domains
• Fibrin binding? Form clot
• Heparin binding? Clot lysis
• Collagen binding? bind where tissues exposed
• Cell surface receptors?hold cells down, this is
  why tissue culture plates are typically coated
  with a thin layer of collagen or fibronectin!
• Collagenase is used when you want to remove cells
  from a culture dish.

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There are several discrete structures that are
observed at the locations where the adherence
molecules bind cells together.
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Two other cell surface receptors

• Basal Lamina found underneath all epithelial
  cells in the body and creates a matrix for
  cellular attachment/protection
• Laminin protein primary constituent
• Large peptide (alpha, beta, gamma subunits)
• Dense packing
• Cross-shape
• Many potential binding domains
• Integrin helps create a link to intracellular
  proteins
• Large dimer (alpha and beta subunits)
• Extracellular aspect- binds matrix or ICAMs
• Intracellular aspect- indirectly binds actin (via
  tallin and vinculin)
• Also an integral part of hemidesmosome
• Extracellular binding is often linked to changes
  in activity of protein kinases in the cytosol

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Cell-Cell adhesions can occur at specifics
locations. What are some of the classic
locations?

• Desmosome button of contact specialized for
  stress!
• Dense deposit of tonofiliments!
• Narrow intercellular space!
• Hemidesmosome attachment to lamina
• Contains tonofilaments,,, sort of ½ of a
  desmosome!
• Adherence Junctions Belt-like or Focal
• Bands of attachement
• Continuity with actin in muscle actin/myosin
  complex
• Tight Junction Protein belt for molecular
  impermeability
• Important where body meets external environment
  gut, skin, kidney
• Gap Junction connexins to allow small molecule
  diffusion between cells.
• Especially important in the heart!

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Often times bacteria and viral particles have
special receptors that fill the receptors on the
cell, causing the host to pull cell inside!

• Once inside pathogen can disable cell!
• Disabled cell is hijacked by the pathogen and
  protected by the cell!
• Examples HIV-Virus, Anthrax, Listeria, Shigella
  and Yersinia
• Most Effective Targets Immune Cells!
• Common Receptor Targets
• Integrin and E-cadherin

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Tight Junctions are critical for maintaining
water impermeability at places where cells meet
the external environment!

• Why are TJ critical in the gut, kidney and skin?
• Where would the water go?
• There is no measurable space between adjacent
  cells bound by TJ!
• TJ Blocks
• 1) .movement of ions, water and proteins between
  these adjacent cell
• 2) .Movement of proteins between the outside
  (apical) and inside (basolateral) aspects of the
  plasma membrane.
• TJ consists of a mesh-like band of thin proteins
  that wrap entirely around cells many many times.
  The proteins (claudins and occludin) of the two
  cells bond to each other pulling the two cells
  very tightly together forming an impermeable
  barrier.

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The claudin and occludin subunits of the two
adjacent cells form a belt around the lateral
aspect of the cell, typically on the apical side.
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Tight Junctions mean that the only way materials
can enter a cell is to pass through the transport
enzymes of the apical membrane, pass though the
cytoplasm, and use a different enzyme on the
baso-lateral membrane. (2 Diff. Tx Enzymes)
This gives a precise way for a cell to regulate
transport!
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Gap Junctions are specialized pores consisting of
two connexons that link the intracellular
contents of adjacent cells. This arrangement
allows small molecules to physically pass between
cell and is especially important in the heart!

• Pores are critical for permitting the movement of
  ions during AP propagation between heart cells!
• Pores create a functional syncitium in the
  heart!
• Connexons may also be important for the passage
  of water, sugars and amino acids.